Unprecedented genetic investigations have found a therapeutic needle in a daunting haystack
Bile helps the intestine break down fat. It is produced in the liver, temporarily stored in the gallbladder and released into the intestine when needed. The series of ducts that helps bile get from one place to another is also the site of a particularly nefarious form of cancer. Officially called cholangiocarcinoma (CCA), bile duct cancer is quite rare, but its incidence is increasing globally, it is highly aggressive and it is resistant to chemotherapy. Furthermore, early CCA is largely asymptomatic, resulting in most diagnosed cases being locally advanced and/or metastatic. Taken together, these characteristics make CCA one of the most fatal cancers, with a median survival time of approximately 12-15 months. With the support of a Marie Skłodowska-Curie Action individual fellowship (MSCA IF), Patricia Munoz-Garrido identified specific genetic pathways pointing to much-needed diagnostic biomarkers and therapeutic targets. Outcomes of her work on the MiRCHOL project while at the Biotech Research and Innovation Centre (BRIC), University of Copenhagen could open the door to personalised or precision medicine and a step change in prognosis for patients with CCA.
Small molecules with outsized influence
Although cancer cells exhibit many abnormalities, their successful proliferation is often linked to a single oncogene. This ‘dependency’ is called oncogene addiction and a large group of small molecules may mediate the effects. MicroRNAs (miRNAs) are non coding RNAs, about 21-24 nucleotides in length, that target specific coding RNAs, inhibiting gene expression. Growing evidence suggests that dysregulation of miRNA expression may play a role in human cancers. “More and better diagnostic and prognostic biomarkers of CCA are urgently needed. A tumour’s ‘oncogenic addiction’ to certain signalling networks mediated by dysregulated miRNA could be the key,” says project coordinator Jesper B. Andersen, also of BRIC. Munoz-Garrido decided to find out.
An unprecedented study leads to unparalleled results
CCA tumours display remarkable molecular heterogeneity and at the same time affect a relatively small number of people, complicating studies tremendously. MiRCHOL conducted miRNA sequencing of the largest patient cohort ever profiled with the help of the miRSeq toolkit. Perseverance paid off. Munoz-Garrido identified many miRNAs that were significantly altered and demonstrated their ability to activate cell proliferation in normal bile duct cell models. Exploiting these discoveries, Munoz-Garrido expounds, “I have identified a very promising therapeutic target, a transcription factor expressed at very low levels in patients with CCA. It orchestrates several gene networks in bile ducts, causing hyperproliferation and enhanced tumour cell viability. Further, it is regulated by one of the top five overexpressed miRNAs with proliferation-inducing activity in cell models.”
From MSCA-IF to commercial R&D
Munoz-Garrido’s MSCA fellowship enhanced her knowledge and expertise in genetic therapy and liver disease and opened the door to new therapies for CCA. It also strengthened her beliefs. “Funding research into rare diseases is imperative to avoid clinical scenarios of no cure or even sustainable treatment for the majority as is seen among patients with CCA today,” says Munoz-Garrido. In her new position at Viralgen Vector Core, a biotech company focused on accelerating the clinical development and commercialisation of life-saving genetic medicines, she is certain to realise her potential and benefit even those who are historically neglected.
Keywords
MiRCHOL, CCA, miRNA, cancer, bile duct, biomarkers, oncogene addiction, transcription factor, cholangiocarcinoma, microRNA